9-13190278-A-G

Variant names:

• chr9-13190278-A-G
• rs149169783
• NM_001378778.1:c.1990T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378778.1(MPDZ):​c.1990T>C​(p.Phe664Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,602,294 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0064 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (7 hom.)
• Consequence: MPDZ NM_001378778.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.330
• Publications: 2 publications found

Genes affected

MPDZ (HGNC:7208): (multiple PDZ domain crumbs cell polarity complex component) The protein encoded by this gene has multiple PDZ domains, which are hallmarks of protein-protein interactions. The encoded protein is known to interact with the HTR2C receptor and may cause it to clump at the cell surface. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2015]

MPDZ Gene-Disease associations (from GenCC):

• hydrocephalus, nonsyndromic, autosomal recessive 2

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0049014986).
• BP6: Variant 9-13190278-A-G is Benign according to our data. Variant chr9-13190278-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00636 (967/152128) while in subpopulation AFR AF = 0.0224 (928/41508). AF 95% confidence interval is 0.0212. There are 14 homozygotes in GnomAd4. There are 438 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378778.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPDZ	NM_001378778.1	MANE Select	c.1990T>C	p.Phe664Leu	missense	Exon 16 of 47	NP_001365707.1
	MPDZ	NM_001375413.1		c.1990T>C	p.Phe664Leu	missense	Exon 16 of 48	NP_001362342.1
	MPDZ	NM_001330637.2		c.1990T>C	p.Phe664Leu	missense	Exon 16 of 47	NP_001317566.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPDZ	ENST00000319217.12	TSL:5 MANE Select	c.1990T>C	p.Phe664Leu	missense	Exon 16 of 47	ENSP00000320006.7
	MPDZ	ENST00000541718.5	TSL:1	c.1990T>C	p.Phe664Leu	missense	Exon 16 of 46	ENSP00000439807.1
	MPDZ	ENST00000447879.6	TSL:1	c.1990T>C	p.Phe664Leu	missense	Exon 16 of 46	ENSP00000415208.1

Frequencies

GnomAD3 genomes AF: 0.00637 AC: 968 AN: 152010 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00161 AC: 388 AN: 240322 AF XY: 0.00117

Gnomad AFR exome AF: 0.0236

Gnomad AMR exome AF: 0.000571

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000364

Gnomad OTH exome AF: 0.000518

GnomAD4 exome AF: 0.000669 AC: 970 AN: 1450166 Hom.: 7 Cov.: 30 AF XY: 0.000587 AC XY: 423 AN XY: 720636

African (AFR) AF: 0.0255 AC: 845 AN: 33200

American (AMR) AF: 0.000845 AC: 37 AN: 43802

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25558

East Asian (EAS) AF: 0.00 AC: 0 AN: 39450

South Asian (SAS) AF: 0.00 AC: 0 AN: 84072

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51424

Middle Eastern (MID) AF: 0.000703 AC: 4 AN: 5688

European-Non Finnish (NFE) AF: 0.00000903 AC: 10 AN: 1106992

Other (OTH) AF: 0.00123 AC: 74 AN: 59980

GnomAD4 genome AF: 0.00636 AC: 967 AN: 152128 Hom.: 14 Cov.: 32 AF XY: 0.00589 AC XY: 438 AN XY: 74354

African (AFR) AF: 0.0224 AC: 928 AN: 41508

American (AMR) AF: 0.00184 AC: 28 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68002

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00284 Hom.: 2

Bravo AF: 0.00695

ESP6500AA AF: 0.0198 AC: 80

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.00194 AC: 234

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 22, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

MPDZ-related disorder Benign:1

Mar 11, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.83	L
PhyloP100		0.33
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.043
Sift	Benign	0.80	T
Sift4G	Benign	0.39	T
Polyphen		0.0010	B
Vest4		0.15
MutPred		0.33		Gain of disorder (P = 0.0845)
MVP		0.17
ClinPred		0.0060	T
GERP RS		1.9
Varity_R		0.069
gMVP		0.14
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs149169783; hg19: chr9-13190277;